Subversion of Pulmonary Dendritic Cell Function by Paramyxovirus Infections

Abstract

Lower respiratory tract infections caused by the paramyxoviruses human metapneumovirus (hMPV) and respiratory syncytial virus (RSV) are characterized by short-lasting virus-specific immunity and often long-term airway morbidity, both of which may be the result of alterations in the Ag-presenting function of the lung which follow these infections. In this study, we investigated whether hMPV and RSV experimental infections alter the phenotype and function of dendritic cell (DC) subsets that are recruited to the lung. Characterization of lung DC trafficking demonstrated a differential recruitment of plasmacytoid DC (pDC), conventional DC (cDC), and IFN-producing killer DC to the lung and draining lymph nodes after hMPV and RSV infection. In vitro infection of lung DC indicated that in pDC, production of IFN-α, TNF-α, and CCL5 was induced only by hMPV, whereas CCL3 and CCL4 were induced by both viruses. In cDC, a similar repertoire of cytokines was induced by hMPV and RSV, except for IFN-β, which was not induced by RSV. The function of lung pDC was altered following hMPV or RSV infection in vivo, as we demonstrated a reduced capacity of lung pDC to produce IFN-α as well as other cytokines including IL-6, TNF-α, CCL2, CCL3, and CCL4 in response to TLR9 stimulation. Moreover, we observed an impaired capacity of cDC from infected mice to present Ag to CD4+ T cells, an effect that lasted beyond the acute phase of infection. Our findings suggest that acute paramyxovirus infections can alter the long-term immune function of pulmonary DC.

Human metapneumovirus keeps dendritic cells from priming antigen‐specific naive T cells

“…10 However, DC infection with hMPV was not shown in this study. 10 Here, we observed that hMPV infects mouse DCs in a restricted and abortive manner, which was characterized by limited expression of virus-encoded proteins, as well as limited production of infectious particles. Despite this fact, DC infection with hMPV rendered these cells inefficient at priming antigen-specific naive T cells, which were not infected by this virus under our experimental conditions.…”

“…33,38 Given that DCs play a major role in naive T-cell priming, several pathogens have evolved molecular mechanisms to impair the function of DCs. 10,31,39 A recent study using antigen-specific mouse T cells showed that conventional DCs isolated from hMPVinfected lungs fail to induce the proliferation of pOVAspecific DO11.10 T cells. 10 However, DC infection with hMPV was not shown in this study.…”

“…10,31,39 A recent study using antigen-specific mouse T cells showed that conventional DCs isolated from hMPVinfected lungs fail to induce the proliferation of pOVAspecific DO11.10 T cells. 10 However, DC infection with hMPV was not shown in this study. 10 Here, we observed that hMPV infects mouse DCs in a restricted and abortive manner, which was characterized by limited expression of virus-encoded proteins, as well as limited production of infectious particles.…”

“…We evaluated whether immature mouse DCs are permissive to hMPV infection by inoculating DCs with variable amounts of infectious (MOI [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] and UV-inactivated hMPV (UV-hMPV). After inoculation, DCs expressing the fusion and nucleoprotein of hMPV could be easily identified by fluorescence microscopy among other noninfected DCs (Fig.…”

“…6,7 These findings suggest that hMPV may have evolved molecular mechanisms to evade host immunity and prevent immune clearance. [8][9][10][11][12] Dendritic cells (DCs) are professional antigen-presenting cells with the unique capacity to activate naive T cells, which later will exert an anti-viral immune response. [13][14][15] Priming of T cells requires DCs to efficiently capture and present viral proteins as antigenic peptide-MHC complexes and to provide co-stimulatory signals needed for full T-cell activation.…”